Glucocorticoids are extensively used in the treatment of inflammatory diseases, like asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases. Glucocorticoids are also keystone drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) (1). Although their use in the treatment of chronic inflammatory diseases and cancer is common, the optimal efficacy is limited by inherent or acquired resistance to the drug. Steroid resistance is also a major problem in the management of patients with inflammatory bowel disease (2). A small number of asthmatic patients do not respond well or at all to corticosteroid therapy (3). Although the issue of glucocorticoid resistance may be less well explored in for instance rheumatoid arthritis than in haematological cancer, the latter two share common mechanisms of resistance, and strategies to overcome resistance after disease treatment will be of mutual interest (7).
The beneficial effects of glucocorticoids are thought to be mediated by suppression of inflammatory gene expression. They act by binding to a single receptor (glucocorticoid receptor, GR) localized in the cytosol of cells. Upon activation, GR translocates to the nucleus where it either switches on (transactivation) anti-inflammatory genes or turns off (transrepression) inflammatory genes (4). Gene induction requires GR dimerisation and DNA binding to specific GR response elements (GREs) located in the promoter region of responsive genes. Glucocorticoids may increase the transcription of genes coding for anti-inflammatory proteins, like lipocortin-1 and interleukin-10. The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes (cytokines, enzymes, receptors and adhesion molecules). The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is an example. The glucocorticoides mediate this inhibitory effect by an interaction between activated GRs and activated transcription factors, such a nuclear factor-κB (NFκB) and activator protein-1 (AP-1), which regulates the inflammatory gene expression. GM-CSF plays a key role in inflammatory and autoimmune disease, and GM-CSF depletion is identified as a separate drug target for suppression of disease symptoms (8).
The use of the glucocorticoides is limited by serious side effects (5), due to their endocrine and metabolic actions, presumably mediated by induced transcriptional regulation of direct GR regulated target genes. The potential adverse effects reported include osteoporosis and suppression of the hypothalamic pituitary-adrenocortical axis, after systemic use, reduction of growth velocity in children, bone mineral loss, occular symptoms and skin changes after inhaled corticosteroid (6). The regulation of transactivation and transrepression, in both a tissue and pathway specific manner, may give improvement of therapeutic index and open for highly selective new corticosteroids (6) with higher therapeutic effect against inflammation or cancer and less side effects due to lower transcriptional regulation of the GR regulated genes of importance for the side effects.
Furthermore, the mechanistic basis also for the anti-cancer effects of glucocorticoids do involve an interaction with GR and it's target genes controlling the expression of cell death/apoptosis proteins.
The cell lines U937 and THP1 are human monocytic/macrophage cells and represent cell line model systems used to test products for anti-inflammatory and anti-cancer activity, the cell lines are also relevant for glucocorticoid resistance, as they are refractory to growth inhibition by dexamethasone and prednisolone (7).
The commonly assigned publication WO98/32718 describes adrenocorticosteroids which may be derivatised with lipophilic groups. Among the compounds mentioned are betamethasone, dexamethasone, and beclomethasone. These derivatised compounds are used to treat inflammation.
Fatty acid conjugates of budesonide, more specifically budesonide oleate, palmitate, linoleate, palmitoleate, and arachidonate have been described. These conjugates are formed during the treatment of inflammation, more specifically asthma, but the fatty acid conjugates of the steroids mentioned are said to be pharmacologically inactive lipoidal conjugates (12).